Identification of a clonally expanding haematopoietic compartment in bone marrow

In mammals, postnatal haematopoiesis occurs in the bone marrow (BM) and involves specialized microenvironments controlling haematopoietic stem cell (HSC) behaviour and, in particular, stem cell dormancy and self‐renewal. While these processes have been linked to a number of different stromal cell types and signalling pathways, it is currently unclear whether BM has a homogenous architecture devoid of structural and functional partitions. Here, we show with genetic labelling techniques, high‐resolution imaging and functional experiments in mice that the periphery of the adult BM cavity harbours previously unrecognized compartments with distinct properties. These units, which we have termed hemospheres, were composed of endothelial, haematopoietic and mesenchymal cells, were enriched in CD150+ CD48? putative HSCs, and enabled rapid haematopoietic cell proliferation and clonal expansion. Inducible gene targeting of the receptor tyrosine kinase VEGFR2 in endothelial cells disrupted hemospheres and, concomitantly, reduced the number of CD150+ CD48? cells. Our results identify a previously unrecognized, vessel‐associated BM compartment with a specific localization and properties distinct from the marrow cavity.     

Incoming RNA Virus Nucleocapsids Containing a 5′-Triphosphorylated Genome Activate RIG-I and Antiviral Signaling

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Highlights? RIG-I is activated by the incoming RNA virus nucleocapsids during infection ? RIG-I activation requires a 5′triphosphate dsRNA structure on the nucleocapsids ? Viral nucleocapsids trigger conformational switching and oligomerization of RIG-I ? RIG-I directly binds to viral nucleocapsids containing a 5′triphosphate dsRNA structure     

Optic Neuritis Is Associated with Inner Nuclear Layer Thickening and Microcystic Macular Edema Independently of Multiple Sclerosis

Background

Microcystic macular edema (MME) and inner nuclear layer thickening (INL) were described in multiple sclerosis (MS) and neuromyelitis optica (NMO) patients using optical coherence tomography (OCT). The cause of these findings is currently unknown and a relation to inflammatory or degenerative processes in the optic nerve is discussed.

Objective

The aim of our study was to investigate whether INL thickening and MME are related to optic neuritis (ON) in various neuro-inflammatory disorders causingON: MS, NMO and chronic inflammatory optic neuropathy.

Methods

We retrospectively analyzed data from 216 MS patients, 39 patients with a clinically isolated syndrome, 20 NMO spectrum disorder patients, 9 patients with chronic inflammatory optic neuropathy and 121 healthy subjects. Intra-retinal layer segmentation was performed for the eyes of patients with unilateral ON. Scanning laser ophthalmoscopy (SLO) images were reviewed for characteristic ocular fundus changes.

Results

Intra-retinal layer segmentation showed that eyes with a history of ON displayed MME independent INL thickening compared to contralateral eyes without previous ON. MME was detected in 22 eyes from 15 patients (5.3% of all screened patients), including 7 patients with bilateral edema. Of these, 21 had a prior history of ON (95%). The SLO images of all 22 MME-affected eyes showed crescent-shaped texture changes which were visible in the perifoveal region. A second grader who was blinded to the results of the OCT classified all SLO images for the presence of these characteristic fundus changes. All MME eyes were correctly classified (sensitivity = 100%) with high specificity (95.2%).

Conclusion

This study shows that both MME and INL thickening occur in various neuro-inflammatory disorders associated with ON. We also demonstrate that detection and analysis of MME by OCT is not limited to B-scans, but also possible using SLO images.     

Evolution of attachment structures in the highly diverse Acercaria (Hexapoda)

Acercaria display an unusually broad array of adhesive devices occurring on different parts of the legs. Attachment structures of all major subgroups are described and illustrated. Nineteen characters of the distal leg region were combined with a data matrix containing 99 additional morphological characters of different body parts. The results of the cladistic analysis are largely congruent with current hypotheses. Zoraptera are not retrieved as close relatives of Acercaria. The monophyly of the entire lineage and of the major subgroups Psocodea, Phthiraptera, and Hemiptera is confirmed. Our data also support the monophyly of Auchenorrhycha and a sister‐group relationship between Thysanoptera and Hemiptera (Condylognatha). In contrast to other lineages of insects, the hairy type of adhesive device is present only in one group within the Acercaria (Heteroptera, Cimicomorpha). The arolium is present in the groundplan but missing in several groups (e.g. Psocodea, Cicadoidea, Aphidoidea). Pretarsal pulvilli evolved several times independently. Tarsal euplantulae and different specialized clasping devices have evolved within Phthiraptera, whereas pretarsal attachment devices are missing in this ectoparasitic group. The potential to modify pretarsal attachment devices in their structural details has probably contributed to the very successful diversification of the predominantly phytophagous Hemiptera.     

Vessel Labeling in Combined Confocal Scanning Laser Ophthalmoscopy and Optical Coherence Tomography Images: Criteria for Blood Vessel Discrimination

Introduction

The diagnostic potential of optical coherence tomography (OCT) in neurological diseases is intensively discussed. Besides the sectional view of the retina, modern OCT scanners produce a simultaneous top-view confocal scanning laser ophthalmoscopy (cSLO) image including the option to evaluate retinal vessels. A correct discrimination between arteries and veins (labeling) is vital for detecting vascular differences between healthy subjects and patients. Up to now, criteria for labeling (cSLO) images generated by OCT scanners do not exist.

Objective

This study reviewed labeling criteria originally developed for color fundus photography (CFP) images.

Methods

The criteria were modified to reflect the cSLO technique, followed by development of a protocol for labeling blood vessels. These criteria were based on main aspects such as central light reflex, brightness, and vessel thickness, as well as on some additional criteria such as vascular crossing patterns and the context of the vessel tree.

Results and Conclusion

They demonstrated excellent inter-rater agreement and validity, which seems to indicate that labeling of images might no longer require more than one rater. This algorithm extends the diagnostic possibilities offered by OCT investigations.     

Effect of methionine-35 oxidation on the aggregation of amyloid-β peptide

Aggregation of Aβ peptides into amyloid plaques is considered to trigger the Alzheimer’s disease (AD), however the mechanism behind the AD onset has remained elusive. It is assumed that the insoluble Aβ aggregates enhance oxidative stress (OS) by generating free radicals with the assistance of bound copper ions. The aim of our study was to establish the role of Met35 residue in the oxidation and peptide aggregation processes. Met35 can be readily oxidized by H₂O₂. The fibrillization of Aβ with Met35 oxidized to sulfoxide was three times slower compared to that of the regular peptide. The fibrils of regular and oxidized peptides looked similar under transmission electron microscopy. The relatively small inhibitory effect of methionine oxidation on the fibrillization suggests that the possible variation in the Met oxidation state should not affect the in vivo plaque formation. The peptide oxidation pattern was more complex when copper ions were present: addition of one oxygen atom was still the fastest process, however, it was accompanied by multiple unspecific modifications of peptide residues. Addition of copper ions to the Aβ with oxidized Met35 in the presence of H₂O₂, resulted a similar pattern of nonspecific modifications, suggesting that the one-electron oxidation processes in the peptide molecule do not depend on the oxidation state of Met35 residue. Thus, it can be concluded that Met35 residue is not a part of the radical generating mechanism of Aβ–Cu(II) complex.     

Patients' and observers' perceptions of involvement differ. Validation study on inter-relating measures for shared decision making

Objective

Patient involvement into medical decisions as conceived in the shared decision making method (SDM) is essential in evidence based medicine. However, it is not conclusively evident how best to define, realize and evaluate involvement to enable patients making informed choices. We aimed at investigating the ability of four measures to indicate patient involvement. While use and reporting of these instruments might imply wide overlap regarding the addressed constructs this assumption seems questionable with respect to the diversity of the perspectives from which the assessments are administered.

Methods

The study investigated a nested cohort (N = 79) of a randomized trial evaluating a patient decision aid on immunotherapy for multiple sclerosis. Convergent validities were calculated between observer ratings of videotaped physician-patient consultations (OPTION) and patients'' perceptions of the communication (Shared Decision Making Questionnaire, Control Preference Scale & Decisional Conflict Scale).

Results

OPTION reliability was high to excellent. Communication performance was low according to OPTION and high according to the three patient administered measures. No correlations were found between observer and patient judges, neither for means nor for single items. Patient report measures showed some moderate correlations.

Conclusion

Existing SDM measures do not refer to a single construct. A gold standard is missing to decide whether any of these measures has the potential to indicate patient involvement.

Practice Implications

Pronounced heterogeneity of the underpinning constructs implies difficulties regarding the interpretation of existing evidence on the efficacy of SDM. Consideration of communication theory and basic definitions of SDM would recommend an inter-subjective focus of measurement.

Trial Registration

Controlled-Trials.com ISRCTN25267500.